T lymphocyte (T cell) activation plays a critical role in immune responses. Deregulation of T cell activation will result in cancer, autoimmune, or immunodeficiency diseases. T cell activation is induced by major-histocompatibility-complex (MHC) molecules on antigen-presenting cells (APC) presenting antigen peptides to T cell receptors (TCR) on the surface of T cells. This stimulation on TCR/CD3 complexes induces a series of signal transduction cascades leading to activation of various kinases such IKK, JNK, and p38. These activated kinases further regulate the activation of multiple transcription factors including NF-?B, NF-AT, and AP-1. These transcription factors ultimately control the gene expression profile in T cells, leading to production of cytokines, and T cell proliferation and differentiation. Recent studies from our lab and others demonstrate that CARMA1, a scaffold molecule, plays a critical role in NF-?B and JNK activation following the stimulation of TCR. Although it is clear that CARMA1 mediates TCR-induced NF-?B activation through regulating I?B kinase (IKK) complex, the molecular mechanism by which CARMA1 is involved in IKK activation is not fully defined. In addition, the role of CARMA1-mediated JNK activation in T cell activation and differentiation remains to be determined. To investigate how CARMA1 is involved in TCR-induced signal transduction and its role in T cell proliferation and differentiation, four specific aims are proposed in this application. The specific aims are: (1) to determine how CARMA1 is recruited into immunological synapse;(2) to determine the signaling pathways mediating TCR-induced IKK activation;(3) to define the role of CARMA1-mediated JNK2 activation in T cell activation and differentiation. These studies will not only reveal the basic mechanism of the TCR-induced signaling pathway, but also provide the molecular insight for determining the unknown causes of autoimmunity, immunodeficiency, and T cell malignancy. Therefore, the results from these studies will provide the molecular basis for designing novel therapeutic agents to treat these diseases. Public Health Relevance Statement: T cell activation and differentiation plays a critical role in immune responses. In this application, we propose to investigate the role of CARMA1 and its associated signaling events in T cell receptor-induced NF-?B and JNK activation that plays pivotal roles for T cell activation and differentiation. The results from these studies will provide the molecular basis for designing novel therapeutic agents to treat autoimmunity, immunodeficiency, leukemia, and lymphoma.